Obesity has been associated with increased incidence of malignancies including colon cancer. As the epidemics of obesity and associated diabetes and metabolic syndrome continue to grow, it is clinically relevant to understand the influence that a steatotic (fatty) liver microenvironment has on the growth of tumors; both metastatic and primary. Preliminary studies show an increased burden of metastatic disease in a mouse model of diet-induced non-alcoholic fatty liver disease (NAFLD). Microarray analysis indicates that the matrix metalloproteinases MMP12 and MMP13 are markedly elevated in the steatotic microenvironment, leading to the hypothesis that tumor cells react to an enhanced host tissue MMP response in the microenvironment of hepatite steatosis and steatohepatitis, which in turn plays a role in dictating the biological behavior of the tumor at its site of metastasis. To test this hypothesis, the specific aims of this proposal utilize mouse models of NAFLD as well as experimental liver metastasis models. In vivo techniques of bone marrow and liver transplantation are proposed to examine cellular mechanisms of action of these MMPs. These are coupled with sophisticated multiphoton microscopy techniques that allow visualization of early metastases in intact mouse livers and analysis of interactions of these tumor cells with the liver microenvironment. Finally, this proposal seeks to determine the molecular mechanisms by which MMP12 and/or MMP13 influences metastatic efficiency in the steatotic liver microenvironment. We hypothesize that MMP-mediated proteolysis of cytokines, chemokines, and/or adipokines establishes microenvironmental cues that influence the survival and establishment of metastatic cancer cells in the steatotic liver. Findings in a mouse model will be corroborated with human liver tissue samples to assure relevance to human disease. The long term objective of these studies is to provide information on the molecular events that contribute to the establishment of colon carcinoma metastasis in the fatty liver that will then lead to more refined targeted therapeutic strategies for the treatment of metastatic colorectal cancer. As a greater percentage of the population lives with NAFLDi the impact of this microenvironment on the growth of metastatic tumors must be better understood. The combination of selective inhibition of stromal and epithelial derived MMPs may become part of rational strategies to treat metastatic colorectal cancer. RELEVANCE (See Instructions): 7 The rising incidence of non alcoholic fatty liver disease (NAFLD) associated with obesity is a problem of increasing clinical significance. In addition, obesity is clinically associated with an increased prevalence of certain malignancies including colon cancer and breast cancer. This proposal seeks to probe the molecular mechanisms by which microenvironmental liver steatosis and steatohepatitis impacts metastasis of colorectal cancer cells to the liver.